Sigma receptors (&#963;Rs), were initially proposed as opioid, and later phencyclidine receptors, and were finally demonstrated to represent unique binding sites in mammalian brain and peripheral tissues that are expressed throughout the CNS and have been implicated in a variety of physiological functions and disease states. Two subtypes of &#963;Rs have been distinguished molecularly and pharmacologically. Although the psychomotor stimulant and reinforcing effects of cocaine are primarily mediated through stimulation of dopamine (DA) neurotransmission by inhibiting dopamine reuptake, cocaine also shows a moderate affinity for &#963;Rs, and it has been suggested that some cocaine-induced effects could be mediated or modulated by its own actions at &#963;1 and/or &#963;2 receptor subtypes. In addition several studies have shown antagonism of various effects of cocaine by &#963;R antagonists, and chronic exposure to cocaine has neuroplastic effects that are prevented by the &#963;R antagonists. Several studies from other laboratories have reported antagonism of cocaine-induced place conditioning by &#963;R antagonists, however, our studies of cocaine self administration indicated a lack of effect of several selective &#963;R antagonists. In the same study, &#963;R agonists produced a leftward shift in the cocaine self-administration dose-effect curve, suggesting that &#963;R agonists would be reinforcing. A test of that hypothesis indicated reinforcing effects of several &#963;R agonists (DTG, PRE-084, (+)-pentazocine) in rats that had been previously trained to self administer cocaine. Subsequent pharmacological studies showed that the self administration of &#963;R agonists was blocked by selective &#963;R antagonists. The antagonism studies thus point to differences in the pharmacology of cocaine and &#963;R agonists self administration in the sensitivity to antagonists. Ongoing studies are further examining the pharmacology of cocaine and &#963;R agonist self administration. The mixed &#963;1/2R agonist DTG and the selective &#963;1R agonist, PRE-084 each stimulate DA neurotransmission. The effects of DTG were antagonized by the preferential &#963;2-receptor antagonist SN79 but not by the preferential &#963;1-receptor antagonist BD1063. In contrast, neither PRE-084 nor cocaine was blocked by either antagonist. Thus, the stimulation of DA by DTG appears to be mediated by &#963;2-receptors rather than &#963;1-receptors whereas that by cocaine or PRE-084 does not likely involve &#963;-receptors. Further, the potency of PRE-084 in stimulating DA was relatively low compared to the reinforcing effects of that compound, suggesting that its reinforcing effects were independent of DA mechanisms. The suggestion that the reinforcing effects of &#963;1R agonists are DA independent is being pursued in pharmacology studies of drug antagonism. Comparable response rates were maintained in two groups of rats: one with cocaine injection as the reinforcer and the other (after a history of cocaine self administration) with PRE-084. As expected cocaine self administration was antagonized by the DA antagonists, SCH 39166, L741,626, and haloperidol. As previously found, cocaine self administration was insensitive to the &#963;R antagonist, BD1063. In contrast, PRE-084 self administration was insensitive to the DA antagonists, SCH 39166 and L741,626, and dose-dependently blocked by the &#963;R antagonists, BD1063. Initial studies indicated that both DTG and PRE-084 were reinforcing in cocaine experienced subjects. We tested whether the &#963;1-receptor agonists, PRE-084 and (+)-pentazocine would reinforce responding in drug nave subjects. Two groups of subjects were allowed to self administer either PRE-084 or (+)-pentazocine for 28 consecutive experimental sessions, a time frame more than sufficient for the acquisition of cocaine self administration. Neither group showed any evidence of reinforcing effects. The doses selected for this study were the doses maintaining maximal response rates in cocaine-experienced subjects. However, the negative outcome may have been due to an inappropriate dose selection. Therefore, we conducted subsequent studies of PRE-084 over a 100-fold range of doses that bracketed the effective doses in cocaine-experienced subjects, and found that PRE-084 failed to maintain responding. The two groups of rats were then given access to cocaine for 14 sessions during which cocaine self administration was acquired. Subsequently both PRE-084 and (+)-pentazocine served as reinforcers. A change in active lever from the right to left lever resulted in subjects increasing responding on the now active and previously inactive lever. Substituting saline for the &#963;1-receptor agonists produced extinction of responding, and allowing access to the &#963;1-receptor agonists again resulted in a re-acquisition of responding. The studies together suggest that a history of cocaine reinforcement induces reinforcing effects of &#963;1-receptor agonists. Additionally, the reinforcing effects of &#963;1-receptor agonists are independent of traditional dopamine reinforcement pathways. These findings further suggest a cocaine-induced plasticity that recruits novel pathways for reinforcing effects that are independent of those found in drug nave subjects, which may contribute to the especially pernicious nature of cocaine abuse and dependence. Previous studies from this laboratory found that rimcazole, a &#963;-receptor antagonist, also binds to the dopamine transporter (DAT) with affinity comparable to its &#963;-receptor affinity. However, this drug exhibited neither cocaine-like psychomotor stimulant nor cocaine-like subjective effects in rodents. Further, rimcazole and several of its analogs attenuate cocaine-induced stimulation of locomotor activity. We recently have demonstrated that rimcazole and selected analogues bind the DAT in a conformation that differs from that for cocaine, which may be related to its lack of cocaine-like in vivo effects. However, the role of &#963;-receptors in the behavioral effects of these compounds remains to be established. Studies of cocaine self administration have also demonstrated that pretreatment with rimcazole analogs selectively blocks the reinforcing effects of cocaine, and that these effects are selective;doses that decrease cocaine self administration have no effect on comparable responding maintained by food reinforcement. Because selective &#963;-receptor antagonists were inactive against cocaine self administration (see above), these findings suggest that the antagonism of cocaine self administration is a combined effect of &#963;R antagonism and actions at the DAT. Studies of combinations of selective DAT inhibitors and &#963;R antagonists support that hypothesis.